Abstract
Inflammasomes are cytosolic caspase-1 activation complexes that sense intrinsic and extrinsic danger signals to trigger inflammatory responses and pyroptotic cell death. Homotypic interactions by Pyrin domains (PYD) and caspase recruitment domains (CARD) in inflammasome component proteins mediate oligomerization into filamentous assemblies. Several cytosolic proteins consisting of only the interaction domains exert inhibitory effects on inflammasome assembly. In this study, we determined the structure of human caspase-1CARD filament by cryo-electron microscopy and investigated the biophysical properties of two caspase-1-like CARD-only proteins, human inhibitor of CARD (INCA or CARD17) and ICEBERG (or CARD18). Our results reveal the surprising finding that INCA caps caspase-1 filament, thereby exerting potent inhibition with low nanomolar Ki on caspase-1CARD polymerization in vitro and inflammasome activation in cells. While caspase-1CARD uses six complementary surfaces of three types for filament assembly, INCA is defective in two of the six interfaces to terminate caspase-1 filament.
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